1. Technical Field
The present invention relates to antisense oligonucleotides and other agents that target nuclear hormone receptors (NHRs) and methods of use thereof.
2. Description of the Related Art
The nuclear hormone receptor (NHR) family of transcription factors bind low molecular weight ligands and either stimulate or repress transcription. See, e.g., V. Laudet et al., The Nuclear Receptor Facts Book, 345, (2002) and (Gronemeyer, Gustafsson et al. 2004)). NHRs stimulate transcription by binding to DNA and inducing transcription of specific genes. NHRs may also stimulate transcription by not binding to DNA but through the modulation of the activity of other DNA binding proteins. This process of stimulation of transcription is called transactivation. NHRs also repress transcription by interacting with other transcription factors or coactivators and inhibiting the ability of these other transcription factors or coactivators from inducing transcription of specific genes. This type of repression is called transrepression (see V. Laudet et al (2002) and (Newton, Leigh et al. 2010).
The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor family of transcription factors, and a member of the steroid hormone family of transcription factors. Glucocorticoids that interact with GR have been used for over 50 years to treat inflammatory diseases. Although glucocorticoids are potent anti-inflammatory agents, their systemic use is limited by numerous side effects. A compound that causes GR to retain the anti-inflammatory efficacy of glucocorticoids while minimizing the side effects such as diabetes, osteoporosis and glaucoma would be of great benefit to a very large number of patients with inflammatory diseases or other conditions. The art is therefore in need of effective and relatively specific modulators of NHRs such as GRs.